Plasma and placental levels of an endogenous cardiotonic steroid MBG are elevated in PE. In vitro low concentrations of MBG stimulate collagen synthesis via activation of protein kinase C-delta and suppression of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. Because levels of MBG in PE are markedly increased, and MBG exerts pro-fibrotic effects, we hypothesized that in PE, elevated placental MBG levels would be associated with development of fibrosis in feto-placental circulation and with impairment of vascular relaxation. We studied 18 patients with PE (mean blood pressure, 1232 mmHg;292 years, 35 wks gest. age) and 12 gestational age-matched normal pregnant subjects. PE was associated with a rise in the levels of MBG in placentae (48.67.0 vs. 13.62.5 nmol/g;P<.01), a 2-fold reduction of erythrocyte Na/K-ATPase activity, a 4-fold decrease in the level of Fli-1 and a 2-fold increase in the levels of procollagen-1 and collagen-1 in the umbilical arteries vs. those in control subjects. As compared to control vessels, isolated rings of umbilical from PE patients, in the presence of unaltered responsiveness to endothelin-1 (EC50 = 20 and 33 nmol/L), exhibited markedly impaired response to the relaxant effect of sodium nitroprusside (EC50= 141 vs. 0.9 nmol/L P<.001) following endothelin-1-induced constriction. Ex vivo incubation of umbilical arteries explants from control subjects with 1-10 nmol/L MBG reduced levels of Fli-1, increased levels of collagen-1, and reduced sensitivity of vascular rings to the relaxant effect of sodium nitroprusside, mimicking the effect of PE. These results demonstrate that in PE, elevated levels of MBG are implicated in vascular fibrosis and impairment of vasorelaxation.